ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3796G>A (p.Gly1266Arg) (rs121907992)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000004053 SCV000192351 pathogenic Wilson disease 2013-12-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000004053 SCV000694454 pathogenic Wilson disease 2017-04-20 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.3796G>A (p.Gly1266Arg) variant involves the alteration of a highly conserved nucleotide. The variant is located within the putative ATP binding site of the conserved P-type ATPase Cu-like domain and 5/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by the functional study, Huster_2012, where G1266R was shown to markedly affect copper transport and abolish catalytic phosphorylation. This variant was found in 6/120738 control chromosomes at a frequency of 0.000049, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant was identified in multiple affected individuals in compound heterozygosity with clinically and biochemically confirmed Wilsons disease (WD). The codon Gly1266 appears to be a mutational hot-spot, as other alteration, such as p.G1266E, p.G1266W and p.G1266V, have been reported in patients with WD. Taken together, this variant is classified as Pathogenic.
Counsyl RCV000004053 SCV000790258 pathogenic Wilson disease 2017-03-23 criteria provided, single submitter clinical testing
Invitae RCV000004053 SCV001205969 pathogenic Wilson disease 2020-07-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1266 of the ATP7B protein (p.Gly1266Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121907992, ExAC 0.01%). This variant has been observed in individual(s) with Wilson disease (PMID: 7626145, 21610751, 11243728). ClinVar contains an entry for this variant (Variation ID: 3849). This variant has been reported to affect ATP7B protein function (PMID: 22240481, 22692182). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000004053 SCV001448794 likely pathogenic Wilson disease 2018-05-11 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001507825 SCV001713634 pathogenic not provided 2020-09-16 criteria provided, single submitter clinical testing PS3, PS4_moderate, PM2, PP1, PP3, PP4, PP5
OMIM RCV000004053 SCV000024219 pathogenic Wilson disease 1995-02-01 no assertion criteria provided literature only
Natera, Inc. RCV000004053 SCV001455582 pathogenic Wilson disease 2020-09-16 no assertion criteria provided clinical testing

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